Role of B-cells and antibodies in Type 1 diabetes
The aim of the proposed project is to understand the role of B cells and alterations of the metabolism in the initiation of Type 1 diabetes development of non-obese diabetic (NOD) mice.
Development of T1D is complex and involves metabolic alterations due to genes, cellular subsets and environmental factors. The initiating event(s) is still to be elucidated, but compelling evidence points to an essential role of B cells as well as metabolic alterations before any signs of autoimmunity is apparent. We have shown that the immune response in NOD is enhanced and prolonged. To elucidate the molecular mechanism of this alteration we plan to test the role of an observed B cell specific altered glycosylation pattern in NOD, focusing on the BCR signaling regulators CD22 and TACI. Also the role of epigentic factors such as transplacental antibodies using embryo transfer systems will be studied.
In addition, we have found that NOD mice have an altered metabolism, including the glutamic acid and nucleic acid components, and this alteration is present long before any evident autoimmune reaction. We will determine the underlying molecular cause for this metabolic defect, and whether it is involved in the development of T1D with functional analysis of proposed involved enzymes as well as challenge the metabolic balance in NOD by metabolite additives, and monitor diabetes development.